Linkage analyses are being conducted in three large pedigrees - designated LMG2, MSUDF1 and HOLON - segregating dominant non- syndromal deafness. Linkage to markers near DFNA1 was detected in the HOLON pedigree (max LOD = 3.7; theta = 0.16). However, the DFNA1 locus itself was excluded, so a new locus designation, DFNA15, was justified. Subsequently, we determined that DFNA15 was a mutant allele (884del8) of the POU4F3 gene, a transcription factor known from mouse knockout models to be important for inner ear development. After excluding linkage to the known DFNA and DFNB loci in pedigree MSUDF1 we initiated a genome-wide screen. After evaluating 80 markers we found significant linkage to markers at 17q25 (LOD = 5.43; theta = 0.0 to marker D17S784). This represents a new DFN locus, and will probably be reported as DFNA18. The proximal flanking marker is D17S802. There is, however, no distal marker at the telomere to define the limits of the region. We are currently evaluating candidate genes in this region by first placing them on a radiation hybrid map relative to D17S802 and D17S784 and then direct sequencing of PCR products from affected and unaffected members of the pedigree. Several members of the LMG2 family have been re-contacted and one phenotype has been reassigned from affected to unaffected on the basis of more recent audiological data. Linkage to known DFN loci has been excluded in pedigree LMG2, and genome-wide screening has been initiated. GJB2 mutations were identified in two Ashkenazi Jewish families segregating non-syndromic recessive deafness. We determined that the carrier frequency for GJB2 mutations was 4.76% in the metropolitan New York Jewish population. Moreover, we found that an allele that is rare in the non-Jewish population, 167delT, is the most common allele among Ashkenazi Jews, with an estimated carrier rate of 4.03%.